Process for the manufacturing of medicaments

Abstract

The present invention provides a process for the manufacture of a compound of formula VIIIa and salts forms of VIIIa where R c is an aryl sulfonic acid

What is claimed is: 
     
         1 . A process for the preparation of a compound of formula VIII, the process comprising the steps of: 
       
         
           
           
               
               
           
         
         (a) contacting 4-bromo-1-chloro-2-fluorobenzene with a metallating agent in an aprotic organic solvent to afford an organomagnesium compound, which is reacted with 2-chloro-N-methoxy-N-methylacetamide to afford 2-chloro-1-(4-chloro-3-fluorophenyl)ethanone (II); 
       
       
         
           
           
               
               
           
         
         (b) contacting II with sodium formate and formic acid in aqueous ethanol to afford 1-(4-chloro-3-fluorophenyl)-2-hydroxyethanone (III) 
       
       
         
           
           
               
               
           
         
         (c) contacting III with a ketoreductase to afford (R)-1-(4-chloro-3-fluorophenyl)ethane-1,2-diol (IV); 
       
       
         
           
           
               
               
           
         
         (d) contacting IV with a silyl chloride (R a ) 3 SiCl and at least one base in a non-polar aprotic solvent to afford (V), and subsequently adding sulfonylchloride R b S(O) 2 Cl to afford VI, wherein R a  is independently in each occurrence C 1-6  alkyl or phenyl and R b  is selected from C 1-4  alkyl or phenyl, optionally substituted with 1 to 3 groups independently selected from C 1-3  alkyl, halogen, nitro, cyano, or C 1-3  alkoxy; 
       
       
         
           
           
               
               
           
         
         (e) contacting 4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (VII) with a strong base in an organic solvent and subsequently adding VI to afford XI; 
       
       
         
           
           
               
               
           
         
         (f) treating XI with an oxidizing agent to afford I; 
       
       
         
           
           
               
               
           
         
         (g) treating 1-methyl-1H-pyrazol-5-amine with a strong base in an aprotic solvent at reduced temperature and adding the compound of formula I to afford IX; and, 
       
       
         
           
           
               
               
           
         
         (h) contacting IX with a de-silylating agent to afford VIII. 
       
     
     
         2 . The process according to  claim 1  wherein the ketoreductase in step (c) affords an enantiomeric excess at least about 98%. 
     
     
         3 . The process of  claim 2  wherein the ketoreductase in step (c) is KRED-NADH-112. 
     
     
         4 . The process of  claim 2  wherein step (c) further comprises NADH or NADPH as a cofactor. 
     
     
         5 . The process of  claim 4  wherein the cofactor is regenerated with a cosubstrate selected from a secondary alcohol or from an additional enzyme selected from alcohol dehydrogenase, glucose dehydrogenase, formatted dehydrogenase, glucose-6-phosphate dehydrogenase, phosphite dehydrogenase or hydrogenase. 
     
     
         6 . The process of  claim 2  wherein the ketoreductase step is performed in an aqueous medium in the presence of organic cosolvent at a temperature between 1 and 50° C. 
     
     
         7 . The process of  claim 6  wherein the ketoreductase step produces a homogeneous suspension. 
     
     
         8 . The process of  claim 1  wherein the silyl chloride is tert-butyldimethylsilyl chloride, the sulfonyl chloride is methanesulfonyl chloride, the bases in step (d) are DMAP and TEA and the non-polar aprotic solvent is DCM and in step (e) the organic solvent is dioxane. 
     
     
         9 . The process of  claim 1  wherein (R a ) 3 Si is tert-butyldimethylsilyl, R b  is methyl, and in step (e) the strong base is potassium hexamethyldisilazane and the organic solvent is diglyme. 
     
     
         10 . The process of  claim 1  wherein in step (a) the metallating agent is i-PrMgCl and LiCl and the solvent is THF, in step (c) the ketoreductase is KRED-NADH-112 and step (c) further comprises the cofactor NAD and the cofactor recycling agent glucose dehydrogenase, in step (d) (R a ) 3 Si is tert-butyldimethylsilyl, R b  is methyl, the bases are DMAP and TEA and the non-polar aprotic solvent is DCM, and in step (e) the strong base is potassium hexamethyldisilazane and the organic solvent is diglyme. 
     
     
         11 . The process of  claim 1  wherein in step (a) the metallating agent is i-PrMgCl and LiCl and the solvent is THF, in step (c) the ketoreductase is KRED-NADH-112 and step (c) further comprises the cofactor NAD and the cofactor recycling agent is glucose dehydrogenase, in step (d) (R a ) 3 Si is tert-butyldimethylsilyl, R b  is methyl, the bases are DMAP and TEA and the non-polar aprotic solvent is DCM, in step (e) the strong base is potassium hexamethyldisilazane and the organic solvent is diglyme, and in step (g) the strong base is potassium hexamethyldisilazane and the aprotic solvent is THF. 
     
     
         12 . The process of  claim 1  wherein in step (a) the metallating agent is i-PrMgCl and LiCl and the solvent is THF, in step (c) the ketoreductase is KRED-NADH-112 and step (c) further comprises the cofactor NAD and cofactor recycling agent is glucose dehydrogenase, in step (d) (R a ) 3 Si is tert-butyldimethylsilyl, R b  is methyl, the bases are DMAP and TEA and the non-polar aprotic solvent is DCM, in step (e) the strong base is potassium hexamethyldisilazane and the organic solvent is diglyme, in step (g) the strong base is potassium hexamethyldisilazane and the aprotic solvent is THF, and in step (h) the desilylating agent is methanolic HCl. 
     
     
         13 . The process according to  claim 1  wherein the compound VIII from step h is contacted with a sulfonicacid in an organic solvent and water to afford a salt of VIIIa where R c  is an aryl sulfonic acid 
       
         
           
           
               
               
           
         
       
     
     
         14 . A process according to  claim 13  wherein R c SO 3 H is benzenesulfonic acid and the solvent is methyl ethyl ketone and water to afford the besylate salt VIIIb. 
     
     
         15 . A process for the preparation of 4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (VII) comprising the steps of: 
       
         
           
           
               
               
           
         
         (a) contacting 2-fluoro-4-iodopyridine with a metallating agent in an aprotic organic solvent to afford an organomagnesium compound, which is reacted with 4-chloro-2(methylthio)pyrimidine in the presence of a palladium catalyst to afford 4-(2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine (X); 
         (b) treating X with potassium tert-butoxide in THF and subsequently with an aqueous acid to afford 4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (VII). 
       
     
     
         16 . The process according to  claim 15  wherein the palladium catalyst is (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II) dichloride, the metallating agent is i-PrMgCl and LiCl, and the aprotic solvent is THF. 
     
     
         17 . The compound (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate. 
     
     
         18 . A pharmaceutical composition comprising (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate and a pharmaceutically acceptable excipient. 
     
     
         19 . Crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate. 
     
     
         20 . Crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an X-ray powder diffraction pattern comprising peaks at 6.16±0.2, 7.46±0.2, 16.36±0.2, 25.76±0.2 and 25.98±0.2 20; or an X-ray powder diffraction pattern substantially as shown in  FIG. 1 ; or an  13 C NMR pattern substantially as shown in  FIG. 19 ; or an  19 F NMR pattern substantially as shown in  FIG. 20 ; or an  19 F NMR pattern comprising peaks at −111.1±0.4 ppm and −115.4±0.4 ppm relative to CFCl 3  (at 293 K); or an  13 C NMR pattern comprising peaks at 157.7±0.2 ppm, 129.6±0.2 ppm, 125.8±0.2 ppm, and 117.0±0.2 ppm relative to tetramethylsilane (at 293 K); or a DSC pattern substantially as shown in  FIG. 2 . 
     
     
         21 . The compound (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid; or crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid; or crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form A; or crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form B. 
     
     
         22 . The compound (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid; or crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid; or crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form I; or crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form II. 
     
     
         23 . Amorphous (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate.